This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Stress is thought to be a major factor underlying maladaptive behaviors associated with cocaine addiction. In both humans and animal models, stress has been shown to cause both increased use and relapse after detoxification. Cocaine withdrawal causes increased anxiety-like behavior as well as other measures associated with stress responses. Corticotropin releasing factor (CRF) is a major coordinator of endocrine, autonomic and behavioral output to stressful stimuli and CRF has been directly implicated in anxiety associated withdrawal from cocaine. The central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) are major extrahypothalamic sources of CRF and both have been shown to play critical roles in behaviors associated with cocaine addiction and stress-induced relapse. The goals of this proposal are to delineate the specific role of CRF from the CeA and BNST on cocaine-induced effects in brain and on behavior. A pharmacological approach coupled with adeno-associated viral vector-mediated RNA interference to knockdown expression of CRF with focal and temporal resolution will allow an investigation of questions related to cocaine reward and relapse. The aims of this proposal are to understand specific aspects of CRF-mediated neural mechanisms underlying maladaptive behaviors associated with cocaine addiction and stress-induced relapse to cocaine seeking.